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Childhood Cancer Treatment and Brain Development

Stress is the focus of Bruce Compas’s research program—and it’s difficult to imagine many things more stressful than a child having cancer. More children are surviving than ever before, but there’s evidence that the aggressive treatments necessary to save lives are affecting children’s long-term cognitive development. Compas is working with other Vanderbilt Kennedy Center researchers to investigate the effects of cancer treatment on cognitive function, to understand the processes underlying neurocognitive effects, and to develop interventions to ameliorate those effects.

Compas, Ph.D., is Patricia and Rodes Hart Professor of Psychology and Human Development and professor of pediatrics.

Cancer is a wide range of diseases with varied prognoses. In children, a common form is leukemia, in which cancer cells are formed in the bone marrow and appear in the bloodstream. Also common are solid tumor cancers, e.g., of the bone or brain. Survival rates have improved dramatically. For example, in leukemia, the survival rate has improved from about 50% to 80-90% in the last 15 years, Compas said.

Earlier, Compas studied stress in adults receiving cancer treatment. In a meta-analysis of studies of effects of chemotherapy on cognitive function in adults, he found that significant effects were demonstrated in roughly 20 different studies. Now Compas is working with researchers in the Vanderbilt- Ingram Cancer Institute and the Vanderbilt Institute of Imaging Science to investigate the effects of pediatric cancer treatment on neurocognitive function.

Led by doctoral student Laura Campbell, Compas and colleagues recently published a secondmeta-analysis establishing the pronounced effects of cancer treatments on children’s neurocognitive function.

Treatment and Cognition

Longitudinal studies of children with brain tumors show that treatment not only affects cognitive function during treatment but also results in continued decline in long-term survivors.

“Surprisingly, there also is a demonstrable effect on brain function in children with leukemia,” Compas said.

In leukemia, survival rates increased after clinicians developed intrathecal chemotherapy, in which powerful drugs are injected into the cerebral spinal fluid in order to protect the brain and spinal fluid from cancer cells.

“The downside is that it has a significant effect on the development of brain tissue and on children’s cognitive function,” Compas said.

A related treatment issue is the delivery of high doses of synthetic steroids, which help manage side effects of chemotherapy as well as growth of cancer cells. A separate line of research has shown that natural steroids, in particular cortisol, are produced at high levels in people who are chronically stressed. Findings indicate that high levels of cortisol over prolonged periods have adverse effects on brain development and function.

“If synthetic steroids at high doses are being administered directly to the brain, that may be as much the culprit as chemotherapy in adversely affecting cognitive function,” Compas suggested. The largest national study of the long-term effects of treatment is the Childhood Cancer Survivorship Study (CCSS), a 13-year multiinstitutional collaboration.

“Children survive, but they struggle with academic performance and later with work and stressors of daily living,” Compas said. “We think one of the reasons is the adverse cognitive effects of treatments.”

Understanding the Neurobiology

Compas is trying to determine whether the regions of the brain affected by chemotherapy are the very regions that help persons manage emotions and cope. His goal is not only to understand and manage the cognitive effects of pediatric cancer treatment but also to better understand how the brain functions in coping with stress.

With funds provided by the Vanderbilt-Ingram Cancer Institute, Compas and colleagues, including psychologists Deborah Van Slyke and Frances Niarhos from the Department of Pediatrics, are investigating the neurocognitive function of pediatric leukemia survivors, compared with matched healthy children. Included are neuroimaging studies to explore where, how, and to what extent brain regions are affected by chemotherapy.

The studies focus on “executive functions”— higher-order, complex thinking and emotion management that require the integration of more basic cognitive functions. The underlying neurobiology of executive function develops during adolescence and continues into early adulthood.

One hypothesis is that chemotherapies cause adverse neurocognitive effects by affecting the growth of neurons, or by causing cell death. Another hypothesis is that treatments are affecting cell myelination—the coating of neurons with a myelin sheath produced by glial cells,making cells more efficient and improving cognitive processing. Continued myelination is thought to be important in the development of executive function. The unique property of chemotherapies is that they identify and kill any rapidly growing cell.

“If glial cells are growing and functioning all the way through adolescence, potentially those cells are getting clobbered by chemotherapy at the same time that synthetic steroids may be affecting grey matter,” Compas said.

Pilot Neurocognitive Studies

Compas and Campbell recently completed neurocognitive testing on about 30 pediatric cancer survivors and a matched group of healthy children. Once again, cancer survivors showed problems in neurocognitive function.

Now Compas and AdamAnderson, Ph.D., associate professor of biomedical engineering and radiology, along with doctoral students Kristen Robison and Erin Rodriguez and undergraduate Honors student Kate Livesay, are using brain imaging methods to investigate neurocognitive function in 12 cancer survivors with poor cognition and 12 matched healthy children.

Children do tasks involving aspects of executive function while their brains are being scanned, using functional magnetic resonance imaging. Included are working memory and inhibition tasks, both of which also provide insight into stress management. A third task explicitly targets coping with stress. Participants are shown an emotionally arousing video clip and then are instructed to think about it in a different way. Compas expects that children with typical cognitive function will be able to reappraise the clip in a way that is calming, while cancer survivors may show impairment in emotion management.

The brain imaging studies also include measures of cell myelination and connectivity among brain regions, using diffusion tensor imaging. “Having a great imaging science institute with cutting-edge technology allows us to pose important clinical questions, which they have the expertise to help us answer,” Compas said. “It’s a great collaboration.”

Related Studies

One of the most difficult things a parent faces is communicating a cancer diagnosis to a child and the possibility of dying. Building on work supported by a VKC Discovery Grant, Compas has received a 5-year grant from the National Cancer Institute with the goal of helping families communicate and cope. VKC investigators Meg Saylor, Ph.D., assistant professor of psychology, andMary Jo Gilmer, Ph.D., associate professor of nursing, are collaborating with Compas.

“We’re examining basic language development in the context of this very stressful life experience and then looking at how neurocognitive development may affect it,” Compas explained.

A line of research with patients with dementia and aging adults provides evidence that regular aerobic exercise positively affects cognitive function and helps deter cognitive decline. Compas plans to test an exercise intervention for pediatric cancer survivors.

Ultimately, Compas and his colleagues are striving to develop better programs for children with cancer and their families to help them cope emotionally and to help rehabilitate the neurocognitive effects of treatment. At the same time, they are working to understand the neurobiology of stress and to develop effective clinical interventions.